Cytokine signals play an essential role in lymphocyte function and development. Disregulation of these signals can impede T cell development and lead to autoimmunity. Recent studies show that individuals possessing mutated cytokine receptor genes exhibit severe immunodeficiency syndromes (XSCID). Many cytokine receptors consist of several chains, some of which are shared between different cytokine receptors. This complexity has made it hard to examine the role of specific cytokines and receptors in different human disease states.The common gamma chain (Gc) is part of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptor complexes. Through its ability to associate with kinases and other molecules, it transduces signals important for lymphocyte function. To examine the role of Gc-mediated signals, mice were generated in which the gene encoding Gc was inactivated by homologous recombination. Examination of these mice demonstrated that lymphocyte development was affected. Although normal populations of T cells, the number of thymocytes was reduced compared to normal thymus. Moreover, we observed an altered CD4/CD8 ratio in the thymus indicating that T cell selection was affected. Peripheral T cells were also affected in Gc-deficient mice. CD8+ cells were consistency low, however, numbers of CD4+ cells increased with age, suggesting a defect in the normal mechanisms of peripheral deletion (apoptosis) of autoreactive cells. While peripheral T cells were functionally unable to respond to TCR engagement, their thymic precursors proliferated in response to TCR engagement. Such findings suggest a role for cytokines in differentially regulating T cell responsiveness vs T cells anergy. B cell development and function was also inhibited. Future experiments will be directed at breeding the Gc-defect into mice expressing transgenes encoding autoreactive antigen receptors. Development of this animal model should be important in understanding the role of cytokines in autoimmune disease and lymphocyte reconstitution. More importantly, these animals provide a model to test therapies directed toward the treatment Gc-mediated immune deficiency in humans. 1. Cao, X, Shores, E.W., et. al. 1995. Immunity 2:223. 2. Leonard, W.J., E.W. Shores, et al. 1995 Immunol. Rev.(in press).